Anxiety’s Ties to Dementia

Dementia doesn’t come
out of nowhere. It’s a consequence of multiple causes, and hunting them down is
an active area of research.

“Because we don’t have
a cure, there’s increasing focus on prevention—identifying modifiable risk
factors,” says Natalie
Marchant, of University College London. “We’ve really hammered down on
vascular risk factors, and now we’re expanding the window of attention to think
about others.”

Compared to depression,
anxiety is somewhat under the radar. But a growing literature suggests that
this more common malady—an estimated one
American in five has an anxiety disorder—is strongly linked to mental
decline as well.

But evidence of an
association raises a vexing question. Anxiety is often part of a dementia prodrome—it
emerges well before cognitive deficits. Does this entirely explain the link, or
might anxiety contribute to, rather than simply reflect neurodegeneration?

For insight into the question, Marchant and
colleagues combed through thousands of studies for those in which clinical
levels of anxiety at midlife were associated with dementia diagnosed at least
10 years later. “We thought if we could expand the time window, we could say
with more confidence that anxiety may actually be a risk factor,” says Marchant.

Only four studies met
the 10-year criteria, but these involved nearly 30,000 people. The findings, reported
this year in BMJ Open: controlling
for depression, highly anxious
individuals were 1.5 to 7 times more likely to develop dementia than
others. “We still don’t know if anxiety is an independent risk factor rather
than just a prodromal symptom, but [our findings] give greater support” she
says.

Inner turmoil

Theories about the
underlying biology are not in short supply. In a 2016 paper,
researchers reviewed evidence suggesting that anxiety disorders accelerate a global
process of cellular aging. A number of studies, the authors noted, associated
anxiety with “neuroprogression,” signs of brain aging that include structural
and functional changes along with reduced neurogenesis and cognitive decline. More
general indications of cell aging, telomere shortening and activated
inflammatory pathways, were also linked to anxiety.

To Marchant, a
“dysregulated hypothalamus-pituitary-adrenal stress response system... is a
biological mechanism worth investigating. We know that chronic elevation of
stress hormones is bad for the brain—it might leave it more vulnerable to AD
[Alzheimer’s disease] pathology. This is a line of research I’d like to
follow,” she says.

Linda Mah,
of Baycrest Health Sciences at the University of Toronto, explored the stress
response-dementia link in some detail in a 2016 review paper
published in Current Opinion in Psychiatry. “Chronic stress and anxiety
affect the brain and body in the same way,” she says. The “fear circuitry” they
share predominantly links the amygdala, limbic system, hippocampus, and
prefrontal cortex [PFC]. Put simply, the experience of fear, stress, or anxiety
activates the amygdala and limbic system. “If the brain is working fine, that
reaction should be dampened after it is no longer appropriate, and the part of
the brain that turns it off is the medial PFC and hippocampus.

“But when people feel
chronic stress or anxiety, the connection between these brain areas is lost;
they can’t talk to each other,” says Mah. “There’s also an alarming change in
structure: shrinking of the hippocampus, and loss of neurons in the PFC.”

These same areas, she
points out, are implicated in dementia. “The hippocampus is the main brain
region in memory formation; if it is shrinking and unable to generate new
neurons, you can’t continue to learn and remember things. Hippocampal atrophy
is one of the more robust biomarkers of AD.”

The entorhinal cortex
(EC), one of the earliest brain regions to change as Alzheimer’s develops,
transmits signals between the hippocampus, PFC, and amygdala, although it is
not part of the fear circuitry. “The EC has not been talked about in regard to
emotional regulation,” Mah says. “I’d be interested in looking at that.”

In the genes

There may be a genetic
element linking anxiety and dementia as well. Using data on 2300 twins from the
Swedish
Adoption/Twin Study of Aging, Andrew Petkus found the usual
association over an unusually long follow-up period— subjects who were more
anxious in middle age were nearly 50 percent more likely to develop dementia an
average of 28 years later.

“Even in individuals
with mildly elevated anxiety, there was an association,” says Petkus,
of University of Southern California.

The analysis paid special attention to twins
who were discordant for dementia—one developed the condition and the other did
not. Among dizygotic pairs, the affected twin was more likely to have had high
anxiety at midlife than the unaffected cotwin. But the association was not
significant for their monozygotic peers.

Because monozygotic
twins are genetically identical while dizygotic twins have just half the same
DNA, “this suggests that there is some genetic factor shared between the risk
for anxiety and dementia,” Petkus says. “Genes common to [the two conditions]
may be explaining some of the association.”

The genetics of both
anxiety and late-onset dementia are clearly complex, involving multiple genes
that each make small contributions to the disorders, he points out. But
identifying those they have in common could lead to new insights into their
underlying neurobiology, and novel treatment approaches.

Mind and brain

Researchers are quick
to reiterate that an association between anxiety and dementia doesn’t prove
causation. “It could be the brains of people at risk of AD in the future are
already more vulnerable to things like stress,” says Mah.

To clarify their
relationship as well as explore therapeutic applications, Marchant and other
researchers are testing whether non-pharmacological interventions to reduce
anxiety will reduce the risk of dementia too. She is leading a clinical trial
of 8 weeks of training in mindfulness and compassion meditation, aimed to
ameliorate health-related fears and anxiety in general among older people with
“‘subjective cognitive decline’—they are highly worried about loss of memory
and thinking, but cognitively intact.

“We are following the
group for 5 years to see if reducing anxiety levels has an impact on cognitive
function and dementia,” she says.

A larger study involving a consortium of
universities across Europe is looking at a similar stress-reduction intervention,
measuring changes in anxiety and other mental health parameters, and using
neuroimaging and blood levels of amyloid and tau protein to track the impact on
the brain.